Nitroalcohols are useful intermediates in organic synthesis for various transformations, especially in the synthesis of 1,2-amino alcohols. The nitroaldol reaction (Henry reaction) involves base-catalyzed addition of nitroalkanes to a carbonyl compound, such as an aldehyde. Certain nitroaldol processes, such as that for producing 3-nitro-4-octanol from 1-nitropropane and valeraldehyde in the presence of an amine, are unacceptably slow from a commercial (economic) standpoint. In particular, even after several hours of reaction time, and even in the presence of large amounts of catalyst, the reaction between 1-nitropropane and valeraldehyde was not complete, or was completed with insufficient purity for further commercial use. Thus, there is a need for a method to improve certain nitroaldol reaction processes in terms of rate and/or purity
There are catalysts that may increase the rate of reaction in a similar manner; however, they are generally costly and frequently lead to increase formation of by-products and unwanted side reactions.
Tetrahedron Report No. 553. entitled The Henry reaction: recent examples and compiled by F. A. Luzzio, (Tetrahedron 57 (2001) 915-945), provides detailed descriptions of many nitroaldol processes performed with various reactants and catalyst systems. While this article mentions that nitroaldol reactions can be accomplished using water as a solvent, such systems typically include surfactants such as benzyltrimethylammonium hydroxide. Furthermore, although several process schemes list water as a component of the catalyst system, the amounts are not sufficient to form a separate phase, in addition to any organic solvent that is present in the system.
Each of U.S. Pat. Nos. 2,151,517, 5,041,691 and 5,962,737 disclose nitroaldol processes performed in single-phase aqueous solvent systems, i.e., without organic solvent. In particular, U.S. Pat. No. 2,151,517 teaches the nitroaldol reaction of nitroparrafins and aromatic aldehydes in aqueous medium with alkali-metal bisulphate as catalyst. U.S. Pat. No. 5,041,691 describes the reaction of nitroalkanes with formaldehyde, catalyzed by potassium hydroxide. U.S. Pat. No. 5,962,737 describes reaction of nitroethane or nitropropane with substituted benzaldehydes, in the presence of tertiary amines, to accomplish stereospecific synthesis of threo isomers of 2-nitro-1-phenylpropanols.
U.S. Pat. No. 5,750,802 also describes the nitroaldol reaction of nitroalkanes with aromatic aldehydes, in the presence of amine catalysts. This reference teaches that while no additional solvent beyond the amine catalyst is required, common solvents, including those containing water, may be used. No mention, however, is made of a two-phase solvent system—organic and aqueous.
Nitroaldol reactions have even been reported in the absence of any solvent, but again, this required use of surfactants. See A. Bhattacharya and V. C. Purohit, Environmentally Solvent-Free Processes: Novel Dual Catalyst System in Henry Reaction, Org. Process Res. & Devel, 2003, 7, pp 254-258.
Successful performance of nitroaldol reactions of aliphatic nitro compounds in aqueous media has also been reported, but required the use of surfactants. See R. Ballini and G. Bosica, Nitroaldol Reaction in Aqueous Media: An Important Improvement on the Henry Reaction, J. Org. Chem. (1997) 62, pp 425-427, and R. Bellini, et al., Recent Developments on the chemistry of aliphatic nitro compounds under aqueous medium, Green Chem., 2007, 9, pp 823-838.